Dimethylaminoalkoxy-di-and tri-methoxy-chalcones and the salts thereof



United States Patent This is a continuation-in-part of the copendingapplication, S.N. 388,003, filed Aug. 6, 1964, and now abandoned.

This invention relates to novel chemical compounds and more particularlyto dimethylaminoalkoxymethoxychalcones and non-toxic acid .solutionsalts thereof.

The dimethylaminoalkoxymethoxychalcones of this invention have thefollowing formula:

R1 0 I C=C- R2 (cnamcmno H v R R3 in which n is 2 or 3, R R R R and Rare hydrogen or methoxy, at least two of R R R R and R being methoxy.

The compounds have antihypertensive properties in the animal organismwhen administered parenterally or orally.

The compounds of this invention may be administered to mammals in anyconvenient dosage unit form with or without diluents, or adjuvants, suchas in the form of pills, tablets, capsules or solutions.

The compounds of this invention are prepared by initially reacting inthe presence of sodium exthoxide a benzaldehyde having the followingformula:

CHO

with a dimethylaminoalkoxy chloride having the following formula:

.(CH N(CH ),,Cl

in which n is 2 or 3. This reaction produces adimethylaminoalkoxybenzaldehyde in accordance with the followingreaction. I

The resulting dimethylaminoalkoxybenzaldehyde is re- 3,407,233 PatentedOct. 22, 1968 ice acted, in the presence of sodium hydroxide, with anacetophenone having the following formula:

in which R R R R and R are hydrogen or methoxy, at least two of R R R Rand R being methoxy. The reaction which occurs is as follows:

0 (l -CH3 Heating of the chalcone prior to purification should beavoided.

If acid addition salts are desired, they are produced by reacting theresulting chalcone with the appropriate acid under anhydrous conditions.For example, if the succinate or malate acid addition salt is desired,succinic acid or malic acid is reacted with the chalcone under anhydrousconditions to produce the required acid addition salt.

Alternatively, the chalcone may be produced by reacting thehydroxybenzaldehyde with the substituted acetophenone. The resultingreaction product may then be reacted with dimethylaminoalkyl chloride inthe presence of sodium ethoxide to produce the desired chalcone.

A more comprehensive understanding of this invention is obtained byreference to the following examples:

Example I.-2-(Z-dimethylaminoethoxy)-3,4,5'-

trimethoxychalcone hydrochloride (A) Z-(Z-dimethylaminoethoxy)benzaldehyde may be prepared by taking -a solution of 2.3 g. (0.1 mole)of sodium in 250 cc. of absolute ethanol and adding 12.2 g. .(0.1 mole)of salicylaldehyde. This solution is refluxed for two hours, afterwhich, the ethanol is removed under vacuum. A solution of 10.8 g. (0.1mole) of p-dimethylaminoethyl chloride in 250 cc. of toluene is added tothe residue and this is refluxed for 4 hours. The mixture is filteredand the filtrate distilled yielding 2-(2-dimethylaminoethoxy)benzaldehyde as distillate.

(B) 17 g. of 2-(2-dimethylaminoethoxy) benzaldehyde and 18.7 g. of3,4,S-trimethoxyacetophenone are dissolved in 50 ml. ethanol and asolution of 5 g. of sodium hydroxide in 5 ml. of water is added. After4-5 hours at room temperature, the reaction mixture is poured on ice andextracted with ether. The ether is dried, filtered and the filtratetreated with a saturated solution of hydrogen chloride in ether. Theprecipitate formed as final product is filtered and recrystallized fromalcohol. The resulting hydrochloride has a melting point of l68170 C.

Example II.2- (Z-dimethylaminoethoxy) -3 ,4',5 '-trimethoxychalconehydrochloride 21.0 gm. of 3,4,S-trimethoxyacetophenone and 12.2 gm. ofsalicylaldehyde are dissolved in ml. of ethanol, and

a solution of 7.1 gm. sodium hydroxide in 12 ml. of water is added.After standing 24 hours at room temperature, the solution is poured intoa mixture of dilute hydrochloric acid and crushed ice and this isallowed to stand for several hours longer. The solid which is obtainedis then filtered and dried. The yellow precipitate is recrystallizedfrom absolute ethanol yielding 25.4 gm. of 2-hydroxy-3',4',5-trimethoxychalcone melting at 135136 C.

25.1 gm. of 2-hydroxy-3',4,5-trimethoxychalcone is added to a solutionof 1.9 gm. sodium in 500 cc. of ethanol and the mixture is refluxed for2 hours. The ethanol is then distilled over and replaced by toluene. Tothis is added 10 gm. of fi-dimethylaminoethylchloride and the mixture isrefluxed with stirring for four hours. The mixture is then filtered andthe filtrate is extracted several times with dilute hydrochloric acid.The acid solution is made basic with sodium carbonate and then extractedwith ether. The ether solution is dried, filtered and the filtrate istreated with a saturated solution of hydrogen chloride in ether. Theprecipitate is filtered and recrystallized from alcohol yielding 12.3 g.of 2-(2-dimethylaminoethoxy)-3, 4',5-trimethoxychalcone hydrochloride,M.P. 168-170 C.

Heating of the final product prior to recrystallization should beavoided.

The following table shows the gross blood pressure changes followingintravenous administration of2-(2-dimethylaminoethoxy)-3,4,5-trimethoxychalcone hydrochloride indogs:

TABLE I Average Changes (mm.) Dose (mg/kg.) N0. Dogs Duration SystolicDiastolic l. 1 0 -15 1 minute. 5 16 51 -49 2 hours. 6 -122 -88Indefinite.

TABLE 2 Average Changes (111111.) Dose (mg/kg.) Duration SystolicDiastolic 5O 41 37 2 hours.

Example III.2-(Z-dimethylaminoethoxy)-3,4'-dimethoxychalconehydrochloride 3,4-dimethoxyacetophenone (5.4 gm., 0.03 mole) and2-(Z-dimethylaminoethoxy) benzaldehyde (5.8 gm., 0.03 m.) are dissolvedin 32 ml. of ethanol. To the ethanol solution is added a solution of 1.9g. of sodium hydroxide in 3.9 ml. of water and the resulting solution isstirred and permitted to stand overnight at room temperature. Thereaction mixture is poured on ice and extracted with ether. The ether isdried, filtered and the filtrate is treated with a saturated solution ofhydrogen chloride in ether. The precipitate is filtered andrecrystallized from isopropanol.

The 2-(Z-dimethylaminoethoxy)-3',4-dimethoxychalcone hydrochlorideproduced has a melting point of 183- 185 C.

A comparison of the calculated composition and elemental analysis of thehydrochloride is as follows:

Analysis.-Calcd. for C H NO Cl: C=64.36%, H 26.68%, N=3.57%. Found:C:64.35%, H:6.8l%, N=.44%.

Example IV .-2 Z-dimethylaminoethoxy) -2',4'-dimethoxychalconehydrochloride 2,4-dimethoxyacetophenone (5.4 gms., 0.03 mole) and2-(Z-dimethylaminoethoxy) benzaldehyde (5.8 gms., 0.03 m.) are dissolvedin 32 ml. of ethanol. To the ethanol solution is added a solution of 1.9g. of sodium hydroxide in 3.9 ml. of water and the resulting solution isstirred and permitted to stand overnight at room temperature. Thereaction mixture is poured on ice and extracted with ether. The ether isdried, filtered and the filtrate is treated with a saturated solution ofhydrogen chloride in ether. The precipitate is filtered andrecrystallized from isopropanol. The2-(Z-dimethylaminoethoxy)-2',4'-dimethoxychalcone hydrochloride producedhas a melting point of 133- A comparison of the calculated compositionand elemental analysis of the hydrochloride is as follows:

Analysis.-Calcd. for C H NO Cl: C=64.36%, H: 6.68%, N=3.57%. Found:C=64.59%, H=6.82%, N: 3.51%.

Example V.--2-(3-dimethylaminopropoxy)-3',4',5'- trimethoxychalconehydrochloride 3,4,S-trimethoxyacetophenone (7.4 g., 0.0352 mole) and2-(3-dimethylaminopropoxy) benzaldehyde (7.35 g., 0.0352 mole) aredissolved in 70 m1. of ethanol. To the ethanol solution is added asolution of 1.9 g. of sodium hydroxide in 3.9 ml. of water and theresulting solution is stirred and permitted to stand overnight at roomtemperature. The reaction mixture is poured on ice and extracted withether. The ether is dried, filtered and the filtrate is treated with asaturated solution of hydrogen chloride in ether. The precipitate isfiltered and recrystallized from isopropanol.

The 2-(3-dimethylaminopropoxy)-3',4',5'-trimethoxychalcone hydrochlorideproduced has a melting point of -177 C.

A comparison of the calculated composition and elemental analysis of thehydrochloride is as follows:

Analysis.Calcd. for C H NO Cl: C=63.37%, H: 6.94%, N=3.21%, Cl=8.13%.Found: C=62.7%, H: 7.22%,N=3.19%,Cl=8.23%.

Example VI.4-(2-dimethylaminoethoxy)-3',4,5'- trimethoxychalconehydrochloride 3,4,S-trimethoxyacetophenone (7.8 gms., 0.0372 mole) and4-(Z-dimethylaminoethoxy) benzaldehyde (7.1 g., 0.0372 mole) aredissolved in 39 ml. of ethanol. To the ethanol solution is added asolution of 1.9 g. of sodium hydroxide in 3.9 ml. of water and theresulting solution is stirred and permitted to stand overnight at roomtemperature. The reaction mixture is poured on ice and extracted withether. The ether is dried, filtered and the filtrate is treated with asaturated solution of hydrogen chloride in ether. The precipitate isfiltered and recrystallized from ethanol.

The 4-(2-dimethylaminoethoxy)-3',4',5'-trimethoxychalcone hydrochlorideproduced has a melting point of 194-196 C.

A comparison of the calculated composition and elemental analysis of thehydrochloride is as follows:

Analysis.Calcd. for C H CINO C=62.62%, H: 6.69%, N=3.32%. Found:C=62.62%, H=6.67%, N: 3.40%.

The 2-(3-dimethylaminopropoxy) benzaldehyde employed in Example V isprepared in the same manner as 2-(Z-dimethylaminoethoxy) benzaldehyde isproduced in Example I except that 12.2 g. (0.1 mole) of'y-dimethylaminopropyl chloride is employed instead of the 10.8 g. of,B-dimethylaminoethyl chloride.

The 4-(2-dimethylaminoethoxy) benzaldehyde of Example VI is prepared inthe same manner that the 2-(2- dlmethylaminoethoxy) benzaldehyde isproduced in Example I except that the same quantity ofp-hydroxybenzaldehyde is employed instead of the salicylaldehyde.

What is claimed is: 1. A chalcone and non-toxic acid addition saltsthereof, said chalcone having the formula:

1 I t t- I H H in which n is 2 or 3 and R R R R and R are hydrogen ormethoxy, at least two and not more than three of said R R R R and Rbeing methoxy.

2. A chalcone or a non-toxic acid addition salt thereof in accordancewith claim 1 in which the dimethylaminoalkoxy group is in the 2 positionof the benzene nucleus, 71 is 2, R R and R are methoxy and R and R arehydrogen, the hydrochloride of said chalcone having a melting point of168170 C.

3. A chalcone or a non-toxic acid addition salt thereof in accordancewith claim 1 in which the dimethylaminoalkoxy group is in the 2 positionof the benzene nucleus, n is 2, R and R are methoxy and R R and R arehydrogen, the hydrochloride of said chalcone having a melting point of183-185 C.

4. A chalcone or a non-toxic acid addition salt thereof in accordancewith claim 1 in which the dimethylaminoalkoxy group is in the 2 positionof the benzene nucleus, 11 is 2, R and R are methoxy and R R and R arehydrogen, the hydrochloride of said chalcone having a melting point ofl33-l34 C.

5. A chalcone or a non-toxic acid addition salt thereof in accordancewith claim 1 in which the dimethylaminoalkoxy group is in the 2 positionof the benzene nucleus, 11 is 3, R R and R are methoxy and R and R arehydrogen, the hydrochloride of said chalcone having a melting point ofl-l77 C.

6. A chalcone or a non-toxic acid addition salt thereof in accordancewith claim 1 in which the dimethylamino alkoxy group is in the 4position of the benzene nucleus, 11 is 3, R R and R are methoxy and Rand R are hydrogen, the hydrochloride of said chalcone having a meltingpoint of l94-l96 C.

References Cited UNITED STATES PATENTS 2/1954 Goldberg et a1. 260570.7XR

U.S. DEPARTMENT OF COMMERCE PATENT OFFICE Washington, D.C. 20231 UNITEDSTATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,407,233 iOctober 22, 1968 Albert M. Packman It is certified that error appears inthe above identified patent and that said Letters Patent are herebycorrected as shown below:

Column 1, line 18, "solution" should read addition Column 6, line 14, "nis 3" should read n is 2 Signed and sealed this 17th day of March 1970.

Attest:

Edward M. Fletcher, Jr. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents I VI I I IIIIII

1. A CHALCONE AND NON-TOXIC ACID ADDITION SALTS THEREOF, SAID CHALCONEHAVING THE FORMULA: